The aim is to develop PET-scan procedures for quantitative studies on the distribution, density and affinity characteristics of D2 receptors in the caudate putamen of healthy volunteers and schizophrenic patients. A substituted benzamide raclopride and its analogues will be used as ligands for PET-scan studies of in vivo binding to C2 receptors. This ligand is superior to previous ligands used in PET-scan studies on dopamine receptors in the living human brain in several respects: (1) high selectivity for D2 receptors; (2) high ratio of specific to non-specific binding in vivo; (3) the possibility to displace binding in vivo by high doses of haloperidol. Studies in healthy volunteers demonstrate that binding of (11C) raclopride to the caudate striatum is saturable. A procedure has been developed, based on saturation analysis, which allows the calculation of Bmax and Kd values in living human subjects. Conventional Hill and Scatchard plots of the data indicate a single class of binding sites and Bmax values of the same order as those obtained in vitro in human autopsy brains. The project aims at comparing healthy human subjects with age matched drug-naive schizophrenic patients. The availability of such patients is guaranteed by our present organization and experience from clinical projects during more than 10 years. The project also aims at analysing the degree of D2 receptor occupancy during treatment of schizophrenic patients with conventional neuroleptic drugs. Preliminary results in haloperidol-and sulpiride-treated patients indicate that more than 90% of dopamine-D2 receptor occupancy is required for optimal antipsychotic effect. This part of the project aims at studying the relationship between dopamine receptor occupancy and therapeutic and side effects of conventional antipsychotic drugs. The project also involves the further optimization of the chemical structure of the ligands. New ligands will be evaluated in studies on brain material from rats, cynomolgous monkeys and deceased human subjects in order to characterize D2 receptor binding. The project also aims at further improving the performance of PET-scan camera systems. Our research aims at improving the resolution power from the present 8 mm to about 4 mm. The new camera system should allow quantitation of dopamine-D2 receptor binding data in limbic and cerebral cortex as well as in large brain stem nuclei (substantia nigra) of living human subjects.